Clopidogrel

The recent US Food and Drug Administration (FDA) "boxed warning" on clopidogrel raises important questions for practitioners and patients. The warning addresses the need for pharmacogenomic testing to identify patients’ altered clopidogrel metabolism and thus their risk for a suboptimal clinical response to clopidogrel. Although there is an expanding database on genetic polymorphisms that may affect clopidogrel metabolism and thus clinical outcomes, there are no evidence-based data upon which todevelop specific recommendations on the role of genetic testing in routine care nor strategies proven to improve the safety/efficacy of specific pharmacologic approaches.
To provide guidance on this issue, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) convened a writing committee. The ACCF and AHA adhere to a rigorous policy regarding relationships with industry and other entities (RWI) of authors and peer reviewers for clinical document development (see http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/Relationships-With-Industry-Policy.aspx). This policy requires that a majority of writing . . . [Full Text of this Article]

clopidogrel-PPI interaction

CLINICAL CARDIOLOGY

Cardiologists shocked by new FDA alert on clopidogrel-PPI interaction

NOVEMBER 17, 2009 | Sue Hughes

Orlando, FL - The FDA has today issued a new public-health warning on the possible interaction between clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and the proton-pump inhibitor (PPI)omeprazole (Prilosec, Procter & Gamble) [1,2]. The alert states: "New data show that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole."

But the timing of the this alert appears peculiar, given that just a few weeks ago, what was said to be the definitive answer to this issue—the only randomized clinical trial on the interaction—was reported, showing absolutely no hint of any reduction in effect of clopidogrel in patients taking omeprazole./.../

Cardiologists contacted by heartwire were surprised at the new FDA announcement.

Plavix

Clopidogrel bisulfate (marketed as Plavix) 
Audience: Cardiovascular healthcare professionals, Pharmacists

FDA notified healthcare professionals that the makers of Plavix have agreed to work with FDA to conduct studies to obtain additional information that will allow a better understanding and characterization of the effects of genetic factors and other drugs (especially the proton pump inhibitors (PPIs)) on the effectiveness of clopidogrel. FDA is aware of published reports that clopidogrel is less effective in some patients than it is in others. Differences in effectiveness may be due to genetic differences in the way the body metabolizes clopidogrel or that using certain other drugs with clopidogrel can interfere with how the body metabolizes clopidogrel. These studies should lead to a better understanding about how to optimize the use of clopidogrel. The FDA recognizes the importance of obtaining these data promptly. The drug manufacturers have agreed to a timeline for completing the studies and FDA will review the new information expeditiously and will communicate its conclusions and any recommendations to the public at that time. It could take several months to complete the studies and analyze the results. Until further information is available FDA recommends the following:

• Healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke.
• Healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC, in patients taking clopidogrel. 
• Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a PPI, including Prilosec OTC.

Read the complete MedWatch 2009 Safety summary, including a link to the Early Communication, at:

http://www.fda.gov/medwatch/safety/2009/safety09.htm#plavix

ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use

Deepak L. Bhatt, MD, FACC, FAHA, et al

This document has been developed by the American College of Cardiology Foundation (ACCF) Task Force on Clinical Expert Consensus Documents, the American College of Gastroenterology (ACG), and the American Heart Association (AHA). Expert consensus documents (ECDs) are intended to inform practitioners, payers, and other interested parties of the opinion of the ACCF and document cosponsors concerning evolving areas of clinical practice and/or technologies that are widely available or new to the practice community. Topics chosen for coverage by ECDs are so designed because theevidence base, the experience with technology, and/or the clinical practice are not considered sufficiently well developed to beevaluated by the formal American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines process. Often the topic is the subject of ongoing investigation. Thus, the reader should view ECDs as the best attempt of the ACCF and other cosponsors to inform and guide clinical practice in areas where rigorous evidence may not be available or the evidence to date is not widely accepted. When feasible, ECDs includeindications or contraindications. Topics covered by ECDs may be addressed subsequently by the ACC/AHA Practice Guidelines Committee as new evidence evolves and is evaluated.

The Task Force on ECDs makes every effort to avoid any actual or potential conflicts of interest that might arise as a result of an outside relationship or personal interest of a member of the writing panel. Specifically, all members of the writing panel are asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest to inform the writing effort. These statements are reviewed by the parent task force, reported orally to all members of the writing panel at the first meeting, and updated as changes occur. The relationships with industry information for writing committee members and peer reviewers are listed in Appendixes 1 and 2, respectively./.../

Clopidogrel-Statin interaction?

Lack of Evidence of a Clopidogrel–Statin Interaction in the CHARISMA Trial Jacqueline Saw, MD*, Danielle M. Brennan, MS, Steven R. Steinhubl, MD, Deepak L. Bhatt, MD, Koon-Hou Mak, MD, Keith Fox, MB, ChB, Eric J. Topol, MD#,* on behalf of the CHARISMA Investigators
* Division of Cardiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio Department of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky Gleneagles Medical Center, Singapore University and Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kingdom# Department of Cardiovascular Diseases, Scripps Clinic, La Jolla, California.
Manuscript received November 7, 2006; revised manuscript received January 19, 2007, accepted January 22, 2007.
* Reprint requests and correspondence: Dr. Eric J. Topol, Director, Scripps Translational Science Institute, Chief Academic Officer, Scripps Health, Professor of Translational Genomics, The Scripps Research Institute, Scripps Clinic, Division of Cardiovascular Diseases, 10666 North Torey Pines Road, Mail Drop SW206, La Jolla, California 92037. (Email: etopol@scripps.edu)

Objectives: The purpose of this study was to evaluate the potential impact of clopidogrel and statin interaction in a randomized, placebo-controlled trial with long-term follow-up.
Background: There are conflicting data regarding whether statins predominantly metabolized by CYP3A4 reduce the metabolism of clopidogrel to its active metabolite and diminish its clinical efficacy.
Methods: The CHARISMA trial was a randomized trial comparing long-term 75 mg/day clopidogrel versus placebo in patients with cardiovascular disease or multiple risk factors on aspirin. The primary end point was a composite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months. We performed a secondary analysis evaluating the interaction of clopidogrel versus placebo with statin administration, categorizing baseline statin use to those predominantly CYP3A4 metabolized (atorvastatin, lovastatin, simvastatin; CYP3A4-MET) or others (pravastatin, fluvastatin; non–CYP3A4-MET).
Results: Of 15,603 patients enrolled, 10,078 received a statin at baseline (8,245 CYP3A4-MET, 1,748 non–CYP3A4-MET) and 5,496 did not. For the overall population, the primary end point was 6.8% with clopidogrel and 7.3% with placebo (hazard ratio [HR] 0.93; p = 0.22). This was similar among patients on CYP3A4-MET (5.9% clopidogrel, 6.6% placebo, HR 0.89; p = 0.18) or non–CYP3A4-MET statin (5.7% clopidogrel, 7.2% placebo, HR 0.78; p = 0.19). There was no interaction between statin types and randomized treatment (p = 0.69). Patients on atorvastatin (n = 4,127) (5.7% clopidogrel, 7.1% placebo, HR 0.80; p = 0.06) or pravastatin (n = 1,440) (5.1% clopidogrel, 7.0% placebo, HR 0.72; p = 0.13) had similar event rates.
Conclusions: Despite theoretic concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration, there was no evidence of an interaction clinically in a large placebo-controlled trial with long-term follow-up.